1. Field of the Invention
Certain well known narcotic analgesics belong to the class of 4,5.alpha.-epoxymorphinan compounds which have the following basic ring system, in which the atoms are numbered as indicated. ##STR2##
The two most familiar compounds of this class are morphine and its 3-methyl ether, codeine, with the structures indicated below. ##STR3##
When the 6-hydroxyl group of each of these compounds is oxidized to an oxo group, the compounds conveniently are referred to as morphinone and codeinone, respectively. When the N-methyl groups of the latter compounds are replaced by other substituent groups they may be referred to as N-substituted normorphinones and norcodeinones, respectively. There are two types of nomenclature commonly used for describing compounds herein. The trivial names, such as morphine or morphinone, are widely accepted and used for the sake of brevity and clarity. The Chemical Abstracts nomenclature is preferred and is used wherever precision is needed. Table A gives the trivial names and Chemical Abstracts names for commonly referred to compounds herein.
Morphine and its relatives are used primarily for the relief of pain (i.e., as analgesics). They are narcotic and possess dependence-inducing ability and produce other side effects that make them less than ideal analgesics (emesis, constipation, sweating, respiratory depressions, miosis). A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist actions which is not morphine-like has potential as an analgesic agent for treatment of moderate to severe pain without liability of drug dependence. Furthermore, a compound having only strong narcotic antagonist action may be a desirable agent for treatment of drug dependence.
TABLE A ______________________________________ NOMENCLATURE Trivial Name Chemical Abstract Name ______________________________________ morphine 7,8-didehydro-4,5.alpha.-epoxy-17- methylmorphinan-3,6.alpha.-diol. morphinone 7,8-didehydro-4,5.alpha.-epoxy-3- hydroxy-17-methylmorphinan-6- one. normorphinone 7,8-didehydro-4,5.alpha.-epoxy-3- hydroxymorphinan-6-one. dihydromorphine 4,5.alpha.-epoxy-17-methylmorphinan- 3,6.alpha.-diol. dihydromorphinone 4,5.alpha.-epoxy-3-hydroxy-17-methyl- morphinan-6-one. codeine 7,8-didehydro-4,5.alpha.-epoxy-3-methoxy- 17-methylmorphinan-6.alpha.-ol. norcodeinone 7,8-didehydro-4,5.alpha.-epoxy-3-methoxy- morphinan-6-one. dihydrocodeine 4,5.alpha.-epoxy-3-methoxy-17-methyl- morphinan-6.alpha.-ol. dihydrocodeinone 4,5.alpha.-epoxy-3-methoxy-17-methyl- morphinan-6-one. ______________________________________
2. Prior Art
The only known 4,5.alpha.-epoxymorphinan compounds possessing substituents other than a hydrogen atom in the 8-position are those with a halogen, nitrogen or oxygen atom at C-8. Yeh, et al. (J. Pharm. Sci. 6: 902 [1976]) report .beta.-halomorphides, i.e., 6,7-didehydro-4,5.alpha.-epoxy-8-halo-17-methylmorphinan-3-ols, which are analgesic compounds. Rapaport and Barber (U.S. Pat. No. 4,054,566; J. Med. Chem. 19: 1175 [1976]) report the preparation of 8-chloro, 8-bromo, and 8-iodocodeinones, used as intermediates in the preparation of codeinone. Seki (Chem. Pharm. Bull. 14: 445 [1966]) has reported various compounds related to codeinone and substituted at the 8-position with a tertiary amine group or a halogen group. Weiss (J. Org. Chem. 12: 1505 [1957]) has reported 8,14-dihydroxy-7,8-dihydromorphinone and the similar codeinone analog. Tada et al. (Tet. Let. [22], 1805 [1969]) have reported 8-hydroxyethoxy-14-hydroxycodeinone and the similar 8-methoxyethoxy analog.
Compounds having a hydrogen atom at the 8-position have also been reported. Dihydrocodeine, dihydrocodeinone, dihydromorphine and dihydromorphinone have long been known (Merck Index, 9th ed., No. 3148, 4672, 3155, 4700). Gates and Montzka (J. Med. Chem., 7: 127 [1964]) have synthesized 7,8-dihydro-17-cyclopropylmethylnorcodeinone, and 7,8-dihydro-17-cyclopropylmethylnormorphinone; the latter compound had narcotic antagonist activity. Telford et al. (J. Pharmacol. Exp. Therap. 133: 106 [1961]; hereafter "TELFORD") reported 7,8-dihydro-N-allylnorcodeinone (17-allyl-4,5.alpha.-epoxy-3-methoxymorphinan-6-one) and disclosed that it had weak analgesic properties.
Additional references which discuss structure-activity relationships in general are: Archer and Harris (Progr. in Drug Research 8: 261 [1965]); Lewis, Bentley and Cowan (Ann. Rev. Pharmacol. 11: 241 [1971]); Kosterlitz and Waterfield (Ann. Rev. Pharmacol. 15: 29 [1975]); and Merz et al. (J. Med. Chem. 20: 844 [1977]).
Small et al disclose in U.S. Pat. No. 2,178,010 (issued Oct. 31, 1939) the reaction of dihydrothebaine: ##STR4## with methylmagnesium iodide in refluxing ether solution for 108 hours to give, after workup which includes acid hydrolysis, a mixture from which may be isolated in 45-58% crude yield (15-17.5% recrystallized) methyldihydrothebainone: ##STR5## and a 9-11% yield (5-6% recrystallized) of isomethyldihydrothebainone: ##STR6##
Small et al. also report in J. Org. Chem., 3, 204 (1938) the reaction of dihydrocodeinone enol acetate: ##STR7## with methylmagnesium iodide for 24 hours in boiling ether to give a 74% yield of V and some VI with no mention of its exact percent yield. It should be noted that the 7-methyl compound VI is the minor product of these reactions and is difficult to obtain.
The introduction of a 7-ketone into the morphinane nucleus with concurrent cleavage of the 4,5-epoxy bond has been reported by Rearick and Gates in Tetrahedron Letters, 507 (1970). They report that treatment of 14-bromocodeinone: ##STR8## with Claisens alkali gives the 7-keto morphinane IX: ##STR9## Sawa et al report the preparation of desoxysinomenine characterized by the formula: ##STR10## and desoxydihydrosinomenine characterized by the formula: ##STR11## in Tetrahedron, 15, 144 (1961) from the naturally occuring alkaloid, sinomenine: ##STR12##
Introduction of 7-substituents on the 4,5-epoxy morphinane nucleus, without cleavage of the epoxy bond has been reported by several workers. Bentley et al report in Chem. Comm., JCS C, 57 (1969) that nitrosyl chloride reacts with thebaine in methanol to give the dimethyl ketal of 7-hydroxyiminoneopinone. Reaction of thebaine with iodine in the presence of AgNO.sub.2 in methanol-chloroform likewise gives the dimethyl ketal of 7.beta.-iodoneopinone.
Lester et al report in Tetrahedron, 20, 1407 (1964) and 21, 771 (1965) that 14-hydroxy-dihydrocodeinone may be converted to the 7-hydroxyimino derivative by reaction with amylnitrite in chloroform containing ethanolic HCl. This compound can be converted to an ethylene ketal and hydrolyzed to the 7-keto-6-ketal which upon further reaction with dimethylsulphoxonium methylide gives the oxirane.